Whether early-stage (N0 neck) oral cancer patients received primary tumor resection without neck dissection benefit from immune checkpoint therapy
Authors: Wei Liu, Xuemin Shen, Linjun Shi, Yue He
Journal: International Journal of Surgery (2023)

Highlights For early-stage oral cancer patients with N0 neck, the therapeutic benefit of neck dissection remains uncertain. Increasing evidence indicates that tumor-draining lymph nodes (LNs) are essential sites for responses to immune checkpoint blockade (ICB) therapy. Surgical removal of the uninvolved LNs was demonstrated to disrupt responses to ICB therapy in mouse models and human patients. For N0 neck oral cancer patients, neck dissection can be approached with caution, particularly in patients receiving ICB immunotherapy. Dear Editor, Oral squamous cell carcinoma (OSCC), representing more than 90% of oral cavity cancer, is characterized by a high risk of neck regional lymph node (LN) metastasis, especially the tumor-draining lymph nodes (tdLNs)1. LN metastases are the most significant prognostic factor for recurrence and survival rate, reducing the survival rate by 50%1. There is a consensus that neck dissection must be considered when apparent node metastasis is clinically found. However, there is still a lack of consensus reached whether patients with early-stage (stages I/II) OSCC with clinical node-negative (N0) neck should receive prophylactic neck dissection at the time of primary tumor resection or they should receive a conservative approach of observation, watchful waiting with therapeutic neck dissection for LN relapse in a timely manner2. Although accumulating evidence indicates that elective neck dissection alongside tumor excision can reduce the risk of regional LN recurrence and improve overall/disease-specific survival compared to observation alone (summarized in Table 1), definitive evidence of its value is lacking due to publication bias and certain limitations mainly being heterogeneity among the studies3–12. Moreover, some clinicians and investigators prefer and recommend an observation policy partly because neck dissection adversely affects patients' quality of life and increases postoperative complications and costs. Neck dissection causes damage to neck structures and might be too invasive for patients with N0 neck; after all, about 70% of early-stage OSCC patients eventually remain node negativity2. Table 1 - Evidence of the systematic review/meta-analysis focusing on elective neck dissection (END) versus observation in OSCC/TSCC in the past 5 years. Main results Author, year Period of studies included Cancer type TNM stage Number of studies included Type of studies Number of patients included Whether END can reduce the risk of regional nodal recurrence Whether END can improve overall/disease-specific survival Akheel et al., 20223 1989–2018 TSCC cT1/2N0M0 37 32 retrospective, 4 prospective, 1 RCT 11 973 Yes No Kumar et al., 20224 1980–2019 OSCC cT1-3N0M0 7 7 RCTs 1250 Yes Yes Oh et al., 20205 1989–2019 TSCC cT1/2N0M0 8 6 RCTs, 2 prospective 1310 Yes Yes Ibrahim et al., 20206 1989–2018 OSCC cT1/2N0M0 24 21 retrospective, 4 RCTs 3809 Yes Yes Cai et al., 20207 1986–2018 OSCC cT1/2N0M0 41 36 retrospective, 5 RCTs 5705 Yes No Cao et al., 20198 1989–2018 OSCC cT1/2N0M0 35 30 retrospective, 5 RCTs 5161 Yes Yes Ding et al., 20199 1980–2015 OSCC cT1-3N0M0 6 5 RCTs, 1 prospective 865 Yes Yes Liu et al., 201910 1990–2018 OSCC cT1/2N0M0 15 13 retrospective, 2 RCTs 3158 No No Chegini et al., 202111 2010–2016 OSCC pT1/2N0M0 13 12 retrospective, 1 prospective 2131 Patients following neck dissection staged pT1-T2N0 with regional nodal recurrence 7.5% (158/2113). A pathologically negative neck does not guarantee against future recurrence. OSCC, oral squamous cell carcinomas; RCT, randomized controlled trial; TSCC, tongue squamous cell carcinomas. Immune checkpoint blockade (ICB) is a monoclonal antibody treatment that blocks coinhibitory receptors on T cells, or their cognate ligands, to elicit heightened antitumor T cell responses. ICB immunotherapy mainly targets the programmed cell death (PD)-1/PD-ligand 1 (L1) axis, and the cytotoxic T-lymphocyte antigen 4 family has revolutionized the therapeutic scenario in oncology13,14. For head and neck cancers, the vast majority of the preclinical and clinical studies on immunotherapy were conducted in locally advanced and recurrent/metastatic head and neck squamous cell carcinomas (HNSCC)15–17. In contrast, few studies on immunotherapy were conducted in early-stage head and neck cancer. Using paired tumor and LN samples [uninvolved (uiLN) and/or metastatic (metLN)] obtained from patients with locally advanced HNSCC, a high-impact study by Rahim et al.18 entitled 'Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes' recently reported that uiLNs play a pivotal role in ICB immunotherapy. Rahim et al.18 identified the progenitor exhausted T (Tpex) cells being a population of CD8+ T cells from uiLNs of human HNSCC in modulating antitumor in response to ICB immunotherapy. Tpex cells are clonally increased in uiLNs and peripheral blood of HNSCC patients following anti-PD-L1 immunotherapy before surgery; these clone cells expanded within the primary tumor, suggestive of migration from tdLNs and differentiation into intermediate exhausted T cells18. Thus, the efficacy of ICB immunotherapy is reliant upon the activation of tdLN-resident lymphocytes, whose subsequent migration to the tumor microenvironment is an essential feature of effective antitumor immunity. Meanwhile, the presence of LN metastases in patients correlated with impaired activation of these T cells within the metLNs and reduced responses to anti-PD-L1 immunotherapy18. This indicates metLNs may be less responsive to ICB owing to suppression of Tpex cell populations, and metLNs removal might prove less consequential than earlier stages where tdLNs still harbor the potential for activation following ICB immunotherapy. LNs are key facilitators of adaptive immunity and harbor vast numbers of potentially tumor-reactive lymphocytes. There is increasing evidence that specific subsets of CD8+ T cells must be recruited from the LNs to the tumor to drive therapeutic responses19. Antitumor immunity and the generation of tumor-specific cytotoxic CD8+ T cells are reliant upon the processes within LNs, which is essential for the efficacy of immunotherapy, and targeting ICB to LNs can enhance efficacy. Indeed, studies in mice and humans have shown that Tpex cells provide a continual reservoir of antigen-specific T cells and robustly respond to ICB immunotherapy19. By targeting anti-PD-L1 to tdLNs, Tpex cell seeding of tumors is increased and the therapeutic response is enhanced. Direct surgical removal of the LNs disrupts responses to ICB in mouse models and human patients19. On the one hand, the procedure removes a reservoir of potentially metastatic cells within metLNs and their immunosuppressive effects, perhaps preventing locoregional LN recurrence and improving progression-free survival. On the other hand, it also removes the main hubs of immune education and tumor antigen presentation in the entire LN basin (both uiLNs and metLNs), thus impeding the capacity of the immune system to generate systemic antitumor immunity and improve overall survival. Therefore, an ideal strategy would likely be to avoid neck dissection for early-stage OSCC patients with N0 neck since the therapeutic benefit of neck dissection remains uncertain. The strategies aimed at eliciting potent antitumor immune responses within LNs hold promise for treating patients with early-stage OSCC and may prove more efficacious than neck dissection in a variety of scenarios. Future immunotherapies would likely benefit from the inclusion of features to specifically target tdLNs, which are essential sites for priming antitumor T cell responses, and they can drive tumor antigen-specific immunity and treat metastatic disease. Collectively, for early-stage OSCC, we argue that neck dissection should be approached with caution, particularly in patients receiving ICB immunotherapy. Hence, it is urgent to assess the design of clinical trials to investigate whether early-stage (N0 neck) OSCC patients who received primary tumor resection without neck dissection benefit from ICB immunotherapy. Ethical approval This work does not include any human/animal subjects to acquire such approval, and then there is not the relevant Judgement's reference number. Sources of funding The authors are supported by the National Natural Science Foundation of China (82170952), Shanghai Municipal Health Commission (2020040457, ZHYYZXYJHZX-202016), and Two-hundred Talent project of Shanghai Jiao Tong University School of Medicine, Innovative Research Team of High-level Local Universities in Shanghai (SHSMUZLCX20212401). Author contribution W.L. and X.S.: data curation, investigation, and writing original draft; L.S. and Y.H.: project administration, conceptualization and writing – review and editing. Conflicts of interest disclosure The authors declare that they have no conflicts of interest. Research registration unique identifying number (UIN) Not applicable. Guarantor Yue He, MD, PhD, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20011, People's Republic of China. Data availability statement The data in this correspondence article is not sensitive in nature and is accessible in the public domain. The data is therefore available and not of a confidential nature.